Cancer associated myositis

FACULTY OF MEDICINE AND HEALTH SCIENCES

Academic Year 2011 - 2012

Cancer associated myositis

Jeroen De Weirdt

Promotor: Prof. Dr. De Bleecker Co-promotor: Dr. De Paepe

Dissertation presented in the 2nd Master year in the programme of

Master of Medicine in Medicine

Table of content

Abstract 1. Introduction

1.1 Diagnosis of IIM 2. Dermatomyositis

2.1 Pathogenesis 2.2 Epidemiology 2.3 Clinical features 3. Polymyositis 3.1 Pathogenesis 3.2 Epidemiology 3.3 Clinical features 4. Inclusion body myositis 4.1 Pathogenesis 4.2 Epidemiology 4.3 Clinical features 5. Other forms of IIM 5.1 Necrotizing autoimmune myopathy 5.2 Overlap syndrome 5.3 Macrophagic myofasciitis 6. Treatment and prognosis 6.1 Treatment 6.2 Prognosis 7. Cancer associated myositis 7.1 Epidemiology

7.1.1 General 7.1.2 Difference in time of diagnosis and cancer 7.2 Prognosis and risk factors of CAM 7.2.1 Clinical features 7.2.2 Association DM/PM and cancer 7.2.3 Autoantibodies 7.3 Screening 7.4 Therapy 7.5 Conclusion

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Abstract

This review article discusses the idiopathic inflammatory myopathies and their relation towards malignancies. The IIM encompass a rare group of systemic diseases characterized by an autoimmune reaction towards the skeletal muscles, inflicting significant morbidity and mortality. Continuous studies on this subject have led to a still developing list of subtypes, each distinguished by characteristic clinical presentations, histopathological findings, and different epidemiological properties. Three major subtypes have been identified for over decades: dermatiomyositis (DM), polymoyositis (PM) and inclusion body myositis (IBM). Differences between these subtypes also affect the risk of developing malignancies; a topic with gained interest over the last decade. The subtypes are strongly related with the probability of developing malignancies and with the type of cancer. Studies conclude that DM is the subtype most associated with malignancy. When diagnosed with a cancer-associated myositis (CAM), clinical course and overall prognosis are adversely affected. Therefore it is of great importance to understand this association, to identify effective screening methods and to determine the risk factors, in order to prevent CAM and its consequences. Autoantibodies play an important role in this, especially considering their positive or negative predictive value. New myositis specific antibodies (MSA) such as the anti-155/140 antibody are being discovered. However, other screening methods are also improving; both in the selection of the screening group based on their risk factors, and in the methodology itself. The current progress in the screening process is based on discoveries regarding the tumor markers such as CA19-9 and CA-125, and on FDG-PET/CT scan. Possible combinations of these methods can increase the screening quality even further. There is no specific treatment for CAM patients, the myositis and the cancer are being treated separately. However, since the course of CAM is more severe, it is of importance to start treatment as soon as possible in order to improve the patient's prognosis. This emphasizes the essential role of a good screening process. Improvement towards evidence-based cancer screening programs in addition to progress in treatment may lead to a significant reduction of the substantial morbidity and mortality patients face today. The search for the causes of CAM is far from over.

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1. Introduction

The IIM are a group of systemic autoimmune diseases, characterized by inflammation of the skeletal muscle. Although IIM are relatively rare, they are a cause of significant morbidity and mortality in those who have the disease. The result of several studies over the years reported an annual incidence between 2.18 and 8.8 patients per million people. [1] The general clinical features are characterized by a varying, progressive degree of muscle weakness that develops subacute (by weeks or months), but in rare cases there is an acute onset. A typical feature is that the patient complains about not being able to do his/or her everyday activities. There are different subtypes of IIM; each with different characteristics. The difference can be made by looking at the clinical, histopathological, immunological and demographic features. On this basis we can differentiate three major subsets: dermatomyositis (DM), polymyositis (PM) and inclusion-body myositis (IBM). Beside these major groups, there are also more rare types of myositis. A proposed classification can be seen in box a.

Box a: proposed classification of idiopathic inflammatory myopathies [2] I Dermatomyositis

Juvenile Adult II Polymyositis III Inclusion body myositis IV Overlap syndromes With polymyositis With dermatomyositis With inclusion body myositis V Other forms: Focal: orbital myositis; localized nodular myositis; inflammatory pseudotumor Diffuse: macrophagic myofasciitis; necrotizing myopathy with pipestem capillaries; infantile myositis VI Cancer-associated myositis

1.1. Diagnosis of IIM

There has always been a lack of uniform diagnostic criteria for IIM. To facilitate the diagnosis, in 1975, the classification criteria of Peter and Bohan were suggested. These criteria are essentially based on clinical features. A presentation of how the Peter and Bohan criteria are now used is illustrated in box b.

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Box b: five major diagnostic criteria to define DM and PM [3] 1. Weakness ? Symmetrical ? Limb-girdle distribution ? Involving anterior neck flexors ? Progressive over weeks or months ? There may be dysphagia ? There may be ventilatory muscle involvement 2. Muscle biopsy evidence of: ? Necrosis of type 1 and 2 fibers ? Phagocytosis ? Regeneration ? Perifascular atrophy ? Inflammatory exudate 3. Elevated muscle enzymes 4. Electrophysiological triad ? Small, short polyphasic units ? Fibrillations, positive sharp waves, insertional instability ? Bizarre high-frequency repetitive discharges 5. Dermatological features ? Heliotrope discolouration of eyelids + periorbital oedema ? Scaly, erythematous dermatitis (Gottron's sign)

Depending upon the number of criteria met, with cutaneous features being a sine qua non of DM, the diagnosis of DM could be considered Definite (three + rash), Probable (two + rash) or Possible (1 + rash). [3]

In addition, over the last couple of years, this diagnostic flow chart has been amended since. Besides the five major criteria, some patients also have serological abnormalities, of which serum autoantibodies (AAB) are the most specific for the disease. AAB characterizing certain forms of IIM have been identified. Two forms of AAB have been distinguished: AAB specific for myositis (MSA) and AAB sometimes associated with myositis (MAA). These terms are rather relative, but generally myositis is the first manifestation in syndromes where MSA has been found. Most often only one MSA can be found in a patient, while there can be one or several MAA [4]. MAA are AAB against nuclear or cytoplasmic antigens, directed against translational transport (antisignal-recognition particle) or against ribonucleoproteins involved in protein synthesis (anti-synthetase). They can be found in roughly 20% of the patients [5]. Some examples are anti-MAS, anti-KJ, anti-Fer, anti-PM-Scl, anti-56kd, anti-RoRNP and anti-U1RNP.

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